FEATURED , Genetics , Genomics , Research

Alan Stolier, MD/

STUDY SUGGESTS BENEFIT OF DRUG TARGETING PIK3CA-MUTATED BREAST CANCER

PIK3CA

Located on chromosome 3, PIK3CA is mutated in approximately 40% of patients with hormone receptor (HR) positive, Her2 negative breast cancer. Standard therapy for these tumors includes hormonal therapy with or without CDK4/6 inhibitors. Because acquired resistance to this therapy is common, new approaches have been sought. 

PIK3CA encodes for a bioactive protein known as PI3K (Phosphoinositide 3- Kinase). Over 30 years of research has confirmed that PI3K signaling contributes to tumorigenesis and is considered a feature of human cancers. The PI3K-AKT (Protein kinase B)-mTOR pathway is often disrupted in cancer cells. Enhanced mTOR activity has an anabolic effect on cells increasing cell growth and cell cycle progression while inhibiting apoptosis. Accelerated signaling of mTOR likely plays a role in tumor cells developing resistance to endocrine therapy. 

It is well known that germline mutations in PTEN (located on chromosome 10 as one might expect) leads to Cowden’s Syndrome with an increased risk of breast, thyroid, and endometrial cancer. It may be less known that somatic mutations in PTEN rank the 2nd most commonly mutated tumor suppressor gene behind TP53! What we also know is that an intact PTEN interferes with the PI3K-AKT-mTOR pathway. In the most simplified of explanations, the frequent inactivation of somatic PTEN allows the PI3k-AKT-mTOR pathway to proceed unimpeded, leading to malignant cell transformation. 

The frequent activation of the PI3K pathway in cancer has made it a logical target for pharmaceutical intervention. Drugs targeting the entire pathway might be ideal but have an adverse toxicity profile. There are also multiple isoforms of PI3K, which can be targeted. Targeting individual forms of PI3K allows high specificity and more reasonable toxicity. 

In a recent article in the New England Journal of Medicine, André et al. presented results of the SOLAR-1 Drugs interfering with the PI3K have several isoforms which are similar but not identical proteins from the same gene. In this study, the researchers evaluated an α-specific PI3K inhibitor, alpelisib, plus fulvestrant in patients with PIK3CA- mutated, HR-positive, HER2-negative advanced breast cancer who had previously been treated with endocrine therapy. This study was a multi-center, multi-national trial that randomized patients with and without mutations in PIK3CA. Both groups received oral alpelisib plus intramuscular fulvestrant. The primary endpoint was progression-free survival.

 

PIK3CA2

Of 1173 patients with interpretable results, 341 had PIK3CA mutations. Of those 341 patients, 169 received fulvestrant plus alpelisib, while 172 received fulvestrant with placebo. The median progression-free survival for patients receiving alpelisib was 11 months vs. 5.7 months for those receiving placebo (p<0.001). At 12 months, the progression-free survival was 46.3% for the alpelisib group vs. 32.9% for the placebo group. The response rate was also higher in the alpelisib group compared to the placebo (26.6% vs. 12.8%). 

 

Unfortunately, there was a significant amount of adverse effects of alpelicib. For those taking alpelicib plus fulvestrant, 63.7% developed hypoglycemia vs. only 9.8% with placebo. Similarly, diarrhea affected 57.7% of the alpelicib group vs. 15.7% for the placebo group. Nausea was half as frequent in the placebo group. Permanent discontinuation of treatment occurred in 71 patients (25%) in the alpelicib due to adverse events. 

 

Conclusions: Alpelicib had activity against advanced breast cancer which has advanced on an aromatase inhibitor. Therefore, the authors suggest that integration of genomic testing for PIK3CA mutation into clinical practice should be considered. In the SOLAR -1 clinical trial, there was noted a strong treatment effect by adding alpelicib to fulvestrant for the previously treated HR-positive, Her2 negative patients.

 

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